Exam 1 material
Exam 1 material NSC 3361
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This 39 page Study Guide was uploaded by Rachael Couch on Thursday February 4, 2016. The Study Guide belongs to NSC 3361 at University of Texas at Dallas taught by Van S Miller in Summer 2015. Since its upload, it has received 154 views. For similar materials see Behavioral Neuroscience in Neuroscience at University of Texas at Dallas.
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Date Created: 02/04/16
Lectures 1 and 2: Neuron and brain anatomy Research on the brain and behavior began in antiquity Aristotle thought the heart was the seat of mental capacities and that the brain’s job was to cool the blood Hippocrates wrote of the brain as the seat of thoughts and emotions Galen (“first neurologist”) reported behavioral changes in braininjured gladiators 4000 B.C – first neuroscience – (euphoriant effect of poppy reported in Sumeria) Phrenology Phrenology studying where different “feelings” come from in the brain Old phrenology o In the 19th century, phrenology assigned separate functions to cortical areas o Bumps on the skull were thought to overlie enlarged brain regions which were matched to behaviors/skills/personality New phrenology still in practice of assigning brain function to brain parts Preview of various topics Dementia front brain shriveled “walnut brain” o Cells dying rapidly; deterioration of the brain Brain development o Newborn baby died; body yellow and brain was colored slightly yellow o High jaundice level turns the brain yellow as well o Kernicterus very rare type of brain damage that occurs in a newborn with severe jaundice Genetic brain disorders o Chromosome 15 abnormality Angelman syndrome – microcephaly (small head because small brain) Multiple sclerosis o White parts on scan are abnormalities autoimmune attack against the brain Movement o Polio shriveled/short right leg; not common anymore because of the vaccine Neuron Doctrine Origin of modern neuroscience The brain is composed of independent cells Signals are transmitted from cell to cell across gaps (synapses) Proposed by Santiago Ramón y Cajal o Used Golgi’s cell staining method to observe neurons Neuron anatomy Neurons have direction; they’re polarized o Directionality allows them to conduct electricity Dendrites – receive information o Have dendritic spines – little “bumps” Dendritic spines increase surface area Have neural plasticity, number and structure are altered by experience Can change over time learning is a physical change in the brain Can be built in about half an hour rapid construction o Brain has everything at hand needed to build the spine Neural plasticity – the process of building and removing dendritic spines The brain is the only organ that has the ability to change (and the immune system); nothing else has plasticity Cell body (soma)– the largest part of a neuron which contains the cell’s nucleus, cytoplasm, and structures that produce proteins, convert nutrient into energy, and eliminates waste; powers everything Axon cable that connects the cell body to the terminal; carries information to other locations Myelin – not part of the neuron; fat wrapped around the neuron; acts as an insulator can be removed; some neurons (most in the CNS) do not have myelin Soma (cell body) Nucleus Rough ER arrays of membranes with ribosomes o Site of protein synthesis for membraneassociated proteins Smooth ER regulates cytoplasm Golgi apparatus stacks of flat membrane compartments o Packages products for shipment in cell Neuron membrane = lipid bilayer = cell membrane o Keeps stuff together; separates the inside from the outside Inside and outside the cell have different charges = charge separator (does NOT power the cell or contain microtubules) o Ion channels restricted flow inside and out; way to “use the charge” o Intrinsic Proteins receptors, ion channels; give neurons the necessary properties for signaling Cytoskeleton network of fibers throughout the cytoplasm o Microtubules 20nm tubes, spirals of tubulin Tracks for movement within neuron; railroad track (axoplasmic transport) Anterograde transport material is moved from soma to terminals along microtubules using kinesin as the enabling protein o Most common transport because proteins made in soma Retrograde transport material is moved from terminals to soma using dynein as the enabling protein Implicated in Alzheimer’s Lissencephaly microtubules unstable and fall apart; unable to transport proteins = Severe pachygyria Lissencephaly – smooth brain; because gyra don’t form Die at young age o Neurofilaments 10nm twisted cables Static support structures; support columns o Microfilaments 5nm double helix of actin Dynamic structures; move things around Associated with cell membrane Mitochondria o MELAS syndrome: Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke Mitochondrial energy failure; mitochondria don’t function properly In any terms of stress (small fever, cold) the mitochondria can’t function, they’re already working really hard to keep up Neuron size Bigger neuron = bigger metabolic ability Larger neurons have more complex inputs and outputs, cover greater distances, and convey information more rapidly Three kinds of neurons (by structure) Unipolar neurons o A single extension that branches in two directions; forming a receptive pole and an output zone o Info travels through axon (flat line) o Doesn’t travel through cell body o Fastest; important in situations where speed is important Ex: sensory neurons; when body is in pain (injury) need fastest response Bipolar neurons o One axon, one dendrite o Usually sensory o In vision; restricted utility; not often used Multipolar neurons o One axon, many dendrites o Most common type o Branches are connections to other neurons o Important when it’s a “multiperson job” o Very slow but allows teamwork – multiple influences (10,000) o In the brain Most neurons are unipolar (CNS) or multipolar (brain); rarely bipolar 3 kinds of neurons (by function) Sensory neurons respond to environment, such as light, odor, or touch Motoneurons (motor neurons) contact muscles or glands o Can activate glands (ex: release of adrenaline) o Work in more than just movement Interneurons (brain) receive input from and send input to other neurons (integration) o Most neurons in CNS are interneurons All neurons have 4 functional zones Input zone (dendrites) o Receiving zone o Neurons collect and integrate information from the environment or other cells Integration zone (axonhillock) o Voting region o The decision to produce a neural signal is made o Ex: in multipolar you have 5000 that say fire, 4999 that say don’t neuron fires signal Conduction zone (axon) o Where information can be transmitted over great distances Output zone (axon terminals) o Neuron talks to other areas/cells – spinal cord to brain Synapses Synapse – connection between 2 neurons Presynaptic – before the synapse Post synaptic– receiver of information Information travels from pre to post synaptic neuron Glial cells “Mothers/caretakers of neurons”; support the brain o NOT neurons; do not fire impulses Astrocytes o Most numerous glial cell in brain o Fill spaces between neurons for support Neurons are separated by a small space (neuron doctrine) which allows room for things to move around because the brain isn’t always stable (hit, shaking, jumping) Astrocytes keep things from moving around too much; keeps things in place o Regulate composition of the extracellular space Control the environment Hangover – caused my too much potassium around the neuron o Astrocytes touch the neuron and the capillary Serves as an intermediary between the two BUT they don’t feed the neuron Oligodendrocytes o Make myelin o Wrap axons with myelin sheaths inside brain and spinal cord 10 or 15 layers of myelin around each axon o Each oligodendrocyte wraps several axons Multiplier effect If an oligo gets killed, then 2 or 3 axons die o Forms segments of myelin sheath; nodes of Ranvier are segments where the axon membrane is exposed No myelin; where the outside of the cell can talk to the inside of the cell; without this gap there would be no conduction of electricity o Myelin deteriorates over time; have to continually wrap it to keep them healthy Ependymal cells o Line ventricles, secrete (make) and absorb cerebral spinal fluid o Only really important before you’re born; help brain development Microglia o Phagocytes (eat cells) that clean up debris from dying neurons and glia Ex: clean up the mess after MS attack o Not from the brain, from the body; make their way into the brain to clean stuff up Glial Cell Problems/Disorders Multiple Sclerosis oligodendrocyte injury from autoimmune attack o Nervous system is particularly prone to autoimmune attacks o White area is where myelin has been attacked by the immune system in random white matter areas Each area heals 90% (not fully) but then within a few months another attack will occur progressive disease o Glial cell disease that effects how neurons work o Treating MS – shut down immune system – causes other potential problems AIDS o Microglial cells and monocytes acquire the virus in an attempt to get rid of it o In the process they become activated o Brain damage occurs from neurotoxins glutamate and NO (nitric oxide) produced by viralactivated microglia o Microglia come in and kill neuron which kills the virus but causes damage because it killed the neuron – but if it doesn’t kill the neuron then you’ll die from the virus The autonomic nervous system Autonomic = automatic; not under voluntary control Not part of the brain; part of peripheral Sympathetic activation prepares the body for action o Chronic pain and stress are linked because they both involve sympathetic nervous system o Gets the body ready to fight – active when mad, scared, etc. o When mellow – the parasympathetic nervous system is active Parasympathetic activation rests and digests o Active when mellow Brain pulsation Brain normally pulses because of blood flow o Blood does not flow like a river; it flows in pulses (heartbeats) If someone’s brain is exposed but is pulsing he can be treated If the brain is not pulsing (even though the heart is beating) then don’t waste your time treating them; they’re not treatable – still true because the brain pressure is too high Types of tissue in the brain White matter –composed of axon bundles o White because myelin sheaths (white fatty tissue) cover the axons o A “bunch of cables” o In MS you would expect white matter to be affected o White matter tracts (axons) connect brain areas Short and long distance connections Connect parts of the brain to each other and the brain to the spinal cord “U fiber” – connects neighboring parts of the brain Gray matter – composed of clusters of cell bodies, have dark gray appearance Areas of the brain Four cortical lobes Temporal – by temples Named brain section off the bone sections that they lie under o Occipital lobe under occipital bone, etc. Parts of the brain Basal ganglia control of movement o “Bunch of neurons o At center of brain – oldest part of the brain o Geometric center of the brain is the thalamus basal ganglia is around the thalamus Thalamus – sensory relay Limbic system – emotional memory, regulation o On top of basal ganglia o Emotional control of movement How to respond when you’re mad/sad etc. o Emotions that effect movement control (limbic system –processes emotion and sends signal to basal ganglia to make you have a facial response Cortex – outermost layer o Has 6 distinct layers (“old cortex” only had 3ish) o Cells in different layers have different functions o Pachygyria Pachy – thick; gyria – gyrus (a fold of the brain) Brain only has 3 layers Child with pachygyria died in infancy If the child had survived – severe mental retardation Thick 2 layer; below cortical layers – white matter Brain stem – automatic region; keeps you breathing when you sleep, etc. o Midbrain – keeps you awake Power button for the brain Includes reticular formation Sleep and arousal, temperature and motor control Coma = problem/damage to reticular formation o Pons – contains motor and sensory nuclei to face o Medulla – heart rate, breathing Transition of brain to spinal cord Cerebellum – movement; motor coordination and learning Meninges Brain protection Dura mater – hard; outermost layer Subdural space o Rupture of vessel in subdural space = subdural hematoma o Blood can continue to compress brain and cause an increase in blood pressure in the brain can be fatal Arachnoid membrane Subarachnoid space o Blood vessels o Filled with CSF Pia mater – soft; thin; closest to brain CSF Cerebral ventricles Ependymal cells in the third and lateral ventricles make CSF (cerebrospinal fluid) o CSF surrounds and cushions the brain o Make a pint of CSF every day Ventricles are empty spaces, filled only with CSF Circulation After production, flows through cerebral aqueduct o Cerebral aqueduct 2mm channel, “water channel” Made of brain tissue, changes shape every time the brain pulsates Exits brain at medulla o Now outside of the brain; the brain is “floating” in CSF; liquid cushion Absorbed into blood system o Goes into blood vessels and now can exit the skull Hydrocephalus – failure in CSF circulation o Cerebral aqueduct not large enough (possibly 1.5mm instead of 2mm) o Increased pressure in the brain; head expanding to compensate o To treat: make a hole to drain the CSF through a straw; VP shunt Neuroimaging Views Horizontal – top view looking down Saggital (midsagittal)– side view Coronal – Front view; head on view o Looks like a crown or butterfly Medial – toward the middle; lateral – toward the side Ipsilateral – same side; contralateral – opposite side Anterior – head end; posterior – tail end Proximal – near center; distal – toward periphery Dorsal – toward the back; ventral – toward the belly To describe the flow of neural information… o Afferent – carries impulses into a region of interest (sensory) Being affected (receiving input) o Efferent – carries impulses away from a region of interest (motor) Causing an effect (causing output) Computerized axial tomography (CT) Xray absorption shows tissue density The denser the tissue, the whiter the image CT is just Xray White – bone (most dense) Black – CSF/fluid least dense Intermediate – brain tissue Magnetic Resonance Imaging (MRI) Process: o Strong magnets cause protons in brain tissue to line up parallel o A pulse of radio waves knocks protons over o Protons reconfigure, emitting radio waves that differ by tissue density Measures the water content Black – bone; no water molecules Outside white – scalp White outside brain – bone marrow; white streak (arrow) Positron emission tomography (PET) Images of brain activity; “functional CT” Uses radioactive chemicals injected into the bloodstream and maps their destination by their emissions Identifies which brain regions contribute to specific functions Not as useful Radioactive – expensive Measure cerebral metabolism; not just structural like CT and MRI Patient with Alzheimer’s – less activity; dead neurons MRI – very fine spatial resolution; PET not as great resolution Functional MRI (fMRI) Most useful detects changes in brain metabolism, like oxygen use, in active brain areas fMRI can show how networks of brain structures collaborate fMRI of blind person reading braille o Visual cortex lights up in blind person – not a visual task; something about language, reading is not just a visual task; they’re “picturing” it in their head? o Different in someone who is born blind (lights up) and someone who is not (can “picture” things) Case: MELAS 14 yo Vietnamese girl at school had a seizure, and on arrival in ER could not move her right arm or see to her left o Could not move right arm = left brain dysfunction On exam, she was quite short and thin, and hard of hearing A month later she was back in ER, this time unable to move her left arm, and her hearing was worse Brain MRI shows stroke on the right side of her brain MELAS – mitochondrial dysfunction Case: Astrocytoma 36 yearold engineer at TI developed incoordination of his left arm and tendency to fall to his left, along with headaches Brain MRI showed white mass at the base of the brain (astrocytoma) o Astrocytoma tumor from proliferation of astrocytes If left untreated he would have died because it’s pressing the brain stem Astrocytoma – most common brain tumor in children Case: Rolf 15 month old boy admitted for continual screaming, vomiting, and enlarging head o Head growing too rapidly because of hydrocephalus; skull growing to compensate from increasing fluid He continued to deteriorate and died 3 weeks later Alexander’s disease – astrocytes fill up with GFAP (glial fibrillary acidic protein), then fail o Untreatable disorder – astrocytes swell up and block the flow of spinal fluid in the brain and causes death White shown on MRI– diffused abnormality of the astrocytes Case: Alex “Our little boy was a good baby; he hardly ever cried. When he was a few weeks old the doctor found cataracts When our son was about four months old, the doctors became concerned about his development. He is now severely retarded” Lowe syndrome defect in Golgi body; proteins not transported; brainbuilding proteins not delivered and therefore not used Metabolic diseases can cause cataracts before birth Cataracts before birth disrupted visual cortex formation Lectures 3 and 4: Neurophysiology Neural Signals The Big Picture: How neurons communicate Under light microscope start with nerve cells, then can zoom in see neurons Under electron microscope, can see the synapse synaptic cleft neuronal membrane ion channel Ionic forces underlie electrical signaling Neurons have a semipermeable membrane (a screen door) Diffusion causes ions to flow from areas of high to low concentration, along their concentration gradient Electrostatic pressure causes ions to flow towards oppositely charged areas (electrical gradient) o Like charges repel/move away from each other Cell membrane The cell membrane is a lipid bilayer Ion channels are proteins that span the membrane and allow ions to pass in and out o Necessary because ions are surrounded by water and the membrane repels water Ion channels are mostly closed (gated) Gated channels open and close in response to… o voltage changes o chemicals (drugs, SSRIs, cocaine) o mechanical action (can be physically pulled open) Resting potential Neurons are just batteries – they store charge to use when needed Inside of the axon is negatively charged (60 millivolts) Outside of the axon is positively charged Dead neuron – if electrode put inside, it would read 0 volts Origin of the resting membrane (equilibrium) potential 2 forces act against each other – electrical and concentration gradient o When these 2 balance = reach equilibrium (force driving in = force driving out) o Charge at equilibrium = 60mV (+ or – 10) Neuronal membranes are not permeable to big negatively charged proteins (anions) o Anions are stuck inside the cell unless the cell dies; cannot pass through membrane negative charge on the inside of the neuron Neurons are selectively permeable to K+ it can enter or leave the cell freely o At rest, K+ ions move into the negative interior of the cell because of electrostatic pressure o As K+ ions build up inside the cell, they also diffuse out along the concentration gradient Prevents all the K+ coming in o K+ reaches equilibrium when ion movement out is balanced by ion movement in o Potassium channel is always open; more inside than outside because the proteins inside are negatively charged + The membrane is slightly permeable to sodium ions (Na ) so they slowly leak in o Sodiumpotassium pump pumps Na out and K in, to maintain the resting potential o 3 sodium out, 2 potassium in – net gain = 1 positive charge o Running the pump requires energy 40% of brain energy is used for pumps o Sodium – always trying to get into cell Na + K + Cl Ca2+ Proteins Outside Cell Many Few Many Many Few Inside Cell Few Many Few Few Many Only thing many of in the cell is K+ and proteins Ion channels are selective filters K+ ions pass through this filter more easily than Na+ o Recall: each ion has its own channel Channelopathy – genetic abnormality of ion channels o Ex: epilepsy, migraine, weakness How is the stored charge used? 2 sections of a neuron: graded potentials and action potential Graded potentials o Occur in dendrites o Neuron is always ready to fire waiting for instructions to do so o Info enters at the synaptic site on the dendrite o Inject positive charge (depolarization) response Could be sodium, calcium, or other positive charge More depolarization = more response “Grades” not all or none – proportionate to intensity of stimulation o As graded potentials spread across membrane, they diminish ”Ripples in a pond” get weaker as they get further away from the source o If membrane reaches threshold (great enough positive charge; 40mV) it triggers an action potential Action Potential o Occurs in axons Starts at axonhillock o Large spike in positive charge o “All or none” neuron fires at full amplitude or not at all “Firing a gun” – either fires or doesn’t o Action potentials increase in frequency with increased stimulus strength o Can fire multiple times as long as it has the charge o Conduction speed is faster on a myelinated axon Unmyelinated axon – slow (10 m/s) Stops at every sodium channel Myelinated axon – rapid; fewer stops; only stops at nodes of Ranvier; myelin covers up any other sodium channels so that conduction doesn’t stop there If node of Ranvier is covered up (which happens in MS where you have to remyelinate), the potential may not be able to reach all the way to the end and so will not fire Also requires less energy to conduct the signal Ionic basis of action potential 1) Voltagegated Na channels (in the axonhillock) open in response to initial depolarization (graded potential) o Increase in amount of Na+ outside of the channel increase in pressure on the gated channel which eventually cause the channel to open o Initial depolarization comes from the opening of sodium channels in the dendrites and soma + o Once it reaches 40mV the Na channels open up o Na+ flow down the concentration gradient to the inside of the cell and along the electrical gradient into the negatively charged cell + 2) More voltagegated channels open and more Na ions enter until membrane potential reaches +40 mV o Na goes past 0 because of the concentration gradient; still less sodium ions inside the cell than outside the cell + 3) Voltagegated Na channels close o At peak, concentration gradient pushing Na ions in equals positive charge (electrical gradient) driving them out + 4) As inside of cell becomes more positive, voltagegated K channels open 5) K moves out and the resting potential is restored Refractory Periods – after firing Limits to how fast the neuron can fire Absolute refractory phase (AR) no more action potentials can be produced o Right after reaching + 40mV; very short o Inactivation gate on sodium channel closes Relative refractory phase (RR) only strong stimulation can produce an action potential o Charge becoming more negative, still not restored o Action potentials are regenerated along the axon o Action potentials travel in one direction (axon hillock to axon terminal) because of the refractory state of the membrane after depolarization Inactivation gate = lock on an axon/ion channel Not the same as closing the channel; block at the cytoplasmic side of the channel Happens during refractory periods and prevents the action potential from firing backwards Multiple ion channels along the axon; can’t go backwards because the door to the left is “locked” Sequence of transmission at chemical synapses 1) Action potential travels down the axon to the axon terminal o The point of an action potential is to get the charge to the terminal 2) At the axon terminal, voltagegated calcium channels open and Ca enters the cell o Wants to get in because no/few calcium ions in the cell (concentration gradient) 3) Synaptic vesicles form in the terminal which transmitter molecules in them and then fuse with membrane and release transmitter into the synaptic cleft 4) Transmitter molecules bind to the postsynaptic receptor causing EPSP or IPSP 5) Transmitter may bind to presynaptic autoreceptors, decreasing release o Feedback regulation 6) After binding, the neurotransmitter is inactivated by: degradation or reuptake o Reuptake Molecules pull the transmitters back into the presynaptic neuron Requires energy o Degradation Breakdown/inactivation of transmitter by an enzyme Example: acetylcholinesterase (AChE) breaks down acetylcholine (Ach) Cuts the molecule in half – gets rid of half and recycles choline Raid blocks AChE – causes excess of Ach excessive twitching Postsynaptic potentials Excitatory postsynaptic potential (EPSP) – small local depolarization, pushing cell closer to threshold o Depolarization = moving the charge closer to 0, making the neuron more likely to fire (60 to 50, etc.+ o EPSPs result from Na ions entering the cell, making inside more positive Inhibitory postsynaptic potential (IPSP) – small local hyperpolarization, pushing cell away from threshold o IPSPs result from Cl ions entering cell, making inside more negative o Hyperpolarization = moving the charge further away from 0, making the neuron less likely to fire (60 to 70, etc.) EPSPs and IPSPs are integrated by the axon hillock – more positive than negative charges fire Electrical Synapses Ions flow directly through large channels into adjacent neurons, with no time delay Benefit: faster, allows neurons to synchronize, saves energy Not common because no control/regulation o If one cell fires, they all fire Ex of electrical synapses: heart – want everybody on the same page at the same time Review: + Transmitter release from presynaptic neuron opens ion channels (e.g., Na ) in postsynaptic membrane. This creates a depolarizing current (EPSP) that passively flows down to axon hillock to trigger action potential that is conducted down the axon to presynaptic terminal and the cycle continues, from toe to brain (or brain to toe) Ligands Ligands fit receptors to activate or block them: lockandkey Any substance that binds a receptor is a ligand Endogenous ligands – neurotransmitters and hormones Exogenous ligands – drugs and toxins from outside the body Ex: Acetylcholine Receptor Number of receptors in a neuron varies over time Drug binds receptor causing it to open up allowing ions to follow through Receptor number changes rapidly – esp. during development, with drug use, learning Upregulation is an increase in number of receptors o Ex.: nicotine receptors when you start smoking o = sensitization (not addiction) Downregulation is a decrease in the number of receptors o Ex.: benzodiazepines (Valium, sleeping pills, etc.) downregulate their receptors o = tolerance (also not addiction) Electroencephalogram (EEG) is a recording of brain potentials: A functional test Records brain potentials/brain waves Normal – waves, mini ups/downs in EEG, neurons talk to each other Abnormal spike in EEG Seizure Disorders Reasons for seizures o Bunches of neurons get together and all fire at the same time; cells are linked, they’re not supposed to be; they’re supposed to be independent operators o They become linked together by an electrical synapse o Drugs – decrease sodium conductance; hyperpolarize Could treat a long seizure with valium (hyperpolarizing) About 2% of people have epilepsy Clinical application – 3 triplets; all with seizures; Na+ channel stays open too long, depolarizes cell neuron more likely to fire o Kids can outgrow seizure because of neuroplasticity o INFC Older onset – less likely to go away because of decrease in neuroplasticity with increased age Generalized (wholebody and wholebrain) convulsions – abnormal activity throughout the brain o Characteristic movements are tonic and clonic contractions Tonic = stiffening, rigid Neurons all firing at once, inhibition lost Clonic = jerking Neurons getting tired, rest then all fire at once, repeated o Unconscious during seizure, entire body involved (entire brain involved) o Seizure is followed by confusion and sleep Neurons not firing after normally, tired – act as if in coma Absence seizure – brain waves show generalized rhythmic activity for a few seconds (much slower than tonicclonic), but hundreds of times a day o No unusual muscle activity, except for stopping and staring o Conscious part of the brain turned off but entire brain not turned off because still able to stand, breathe, etc. Entire brain without motor activity o Events during seizure are not remembered o Childhood onset, kids outgrow it, the brain makes the right types of receptors o Neurons fire 3 times/sec instead of 810/seconds like normal Partial seizures o Do not involve entire brain o Start in one area o May have jerking of one side o Can start in one hemisphere and during the seizure transfer to other hemisphere (travel across corpus callosum) o Right face twitching – defect in left hemisphere motor cortex o Reason it’s different from a tick is that it’s rhythmic o Simple partial seizure – normal awareness; can last for days/weeks o Complex partial seizure – impaired awareness; unaware Myoclonic seizures o Rapid, brief contractions of bodily muscles, which usually occur at the same time on both sides of the body o Myo – muscle; clonic – jerk o Chance of severe mental retardation – 98% Types of seizures o Partial onset Simple partial – only seizure with normal awareness Complex partial o Generalized onset Absence seizures (petitmal) Myoclonic seizures Generalized tonicclonic seizures (grandmal) Case: Fugu (pufferfish) A 32yearold man ate three bites of fugu, and then noticed tingling in his tongue and right side of his mouth followed by a "light feeling," anxiety, and "thoughts of dying." He felt weak and then collapsed. Collapse because he can’t breathe – respiratory paralysis; tetrodotoxin (made by pufferfish) – made in the internal organs, have to be cleaned out and thrown away Tetrodotoxin blocks sodium channels, have to have sodium in cell to fire the breathing muscles/diaphragm Tetrodotoxin blocks nerve action by binding to / blocking pores of voltagegated, sodium channels in neuron membranes Lectures 5 and 6: Neurotransmitters and neuropharmacology Ligands bind to two main classes of receptors Ionotropic – direct; ligand binds to ion channel which opens up a pore in the membrane o = Ligandgated ion channel Metabotropic –indirect; ligand binds to a receptor which causes some intermediate (usually a G protein) to dissociate from the receptor (inside the cytoplasm) and bind the ion channel causing it to open o Ion channel is near ligandbinding site but not next door o Often many intermediates, cascade of binding to open the channel Many places to target for drug therapeutics o More complex so more likely to go wrong o Used more often in the brain than ionotropic Agonist Anything that acts like the natural ligand Initiates normal effects of the receptor Antagonist Blocks the natural action of the ligand Competitive – compound competes with the natural ligand for the active site o When compound is bound no signal Noncompetitive – compound binds in site other than the active site o Either natural ligand can still bind partial signal o Or compound prevents ligand from binding in an indirect way o Most drugs are noncompetitive Both competitive and noncompetitive are temporary effects; reversible Neurotransmitters Chemicals that affect synaptic transmission by increasing or decreasing the chance of the neuron firing Classes of neuro transmitters Amino acids glutamate, aspartate, glycine, GABA (gagG) Monoamines o Catecholamines dopamine, epinephrine, norepinephrine o Indolamines serotonin Soluble gases nitric oxide and carbon monoxide Acetylcholine Neuropeptide endorphins Amino acids: Glutamate Most common excitatory neurotransmitter in the brain Glutamate binds to a receptor causing a sodium channel to open Ionotropic glutamate receptors o AMPA, NMDA, and kainite Metabotropic glutamate receptors o mGluRs (G proteincoupled receptors) Excitotoxicity – neural injury such as stroke or head trauma causes the excessive release of glutamate, which kills neurons Glycine The major inhibitory neurotransmitter in the spinal cord Strychnine blocks glycine and causes death o Symptoms appear within 20 minutes First neck stiffness, twitching muscles, and feeling of suffocation Later violent convulsions with body arched and head bent backward o After a minute muscles relax, but a touch or noise causes convulsions to recur, or they recur spontaneously, every few minutes o Do not lose consciousness = agonizing, fullyaware death o Rat poison has strychnine o Strychnine is a way to induce tetanus GABA Most common inhibitory neurotransmitter in the brain GABA iA an ionotropic gated Cl channel o Produces fast inhibitory effects GABA agonists, like valium and barbiturates, are potent tranquilizers o First drug of choice for a seizure is a GABA agonist o Very simple and likely to work because ionotropic GABA has a binding site for valium because the brain naturally makes its own valium Ethanol binds GABA o Too much alcohol binds to the GABA receptor and acts as a depressant Monoamines: Catecholamine synthesis Synthesized from tyrosine (from almost every food) Tyrosine hydroxylase (which converts tyrosine to an intermediate) is ratelimiting Intermediate dopamine –(enzyme) norepinephrine—(enzyme) epinephrine o If dopamine is never made then norepinephrine and epinephrine cannot be made Dopamine Made at the top of the brain stem then spreads throughout the brain Dopamine is involved in reward, addiction, reinforcement and learning, and schizophrenia Dopamine is projected into the basal ganglia and effects motor control o Involved in Parkinson’s disease Norepinephrine Made in the locus coeruleus (meaning blue spot) and spreads out in the brain o Starts in a line down the back of the brain stem Involved in mood, arousal, sexual behavior Serotonin Synthesized throughout the brain stem (scattered origins) and the spinal cord then spreads all over the brain Similar to norepinephrine Involved in sleep, mood, sexual behavior, anxiety, and depression Soluble gases/gas transmitters Nitric oxide (NO) is produced in dendrites and diffuses immediately Gases cannot be stored in the membrane because they diffuse through it o Can store dopamine, norepinephrine, etc. in a vesicle Serves as a retrograde transmitter by diffusing back into presynaptic neuron o Made in the postsynaptic neuron and diffuses to provide feedback to the presynaptic neuron Acetyl Choline Cholinergic pathways in the brain o Made in the basal forebrain = bottom of the brain (not the brain stem) Basal forebrain (thinking, memory, reasoning, intellect, emotion…) o Alzheimers begins in the basal forebrain acetyl choline is the first to be affected First function to be affected is thinking 2 kinds of receptors: nicotinic and muscarinic Nicotinic o Ionotropic o Excitatory o Peripheral in muscle (not brain) o Agonist Nicotine Binds and opens it allowing sodium to come inside the cell o Antagonist – Curare Curare paralysis but would not lose consciousness because receptors are not in the brain Muscarinic o Metabotropic o Can be excitatory or inhibitory o CNS – receptors in the brain o Agonist Muscarine o Antagonist – Atropine, scopolamine, Benadryl, cough/cold medicines that make you dizzy Alter cognition Neuropeptide Endogenous opiates – enkephalins, endorphins, dynorphins o Peptides that bind to opioid receptors and relieve pain (analgesics) o Addictive Endorphins are produced by the pituitary and hypothalamus during exercise (stressful/intense – marathon running, etc.), excitement (extreme excitement), pain, eating spicy food, love, and orgasm Endogenous opiates produce analgesia and a feeling of wellbeing o Any action that stimulates endogenous opiates can be addictive Neuromodulators Indirectly affect transmitter release or receptor response Adenosine o Normally released with catecholamines (dopamine and norepinephrine) o Inhibits catecholamine release via presynaptic autoreceptors o During wakefulness adenosine builds up, making us sleepy Caffeine o Blocks the effect of adenosine stimulates catecholamine release, causing arousal o Greater than 50% increased mortality risk in young people who drank more than 4 cups of coffee per day Sites of drug action Drugs can affect multiple sites like transport of molecules into the synapse, synthesis, storage of compounds… Ex: Low blood pressure drug causes “leaky” storage of adrenaline – which causes increase in blood pressure Drugs Antipsychotic (neuroleptic) drugs Class of drugs to treat schizophrenia, aggressive behavior, psychosis, and OCD Used in all ages, even young children that show excessive psychotic behavior Typical neuroleptics are dopamine (D )2antagonists Blocking the dopamine makes people calmer and more lucid o Accidentally discovered its use for schizophrenia when treated patient to prevent them from harming themselves/others Antidepressants Mostly act by causing the accumulation of monoamines 3 classes of antidepressants, only 2 used now o Each class became increasingly selective decreased side effects MAOIs Monoamine oxidase inhibitors prevent the breakdown of all monoamines at the synapse o Monoamine oxidase breaks down monoamines (serotonin, adrenaline, epinephrine) o An accumulation of adrenaline can be dangerous because inc. blood pressure o Not used anymore Tricyclics increase norepinephrine and serotonin at synapses by blocking their reuptake into presynaptic axon terminals SSRIs Selective serotonin reuptake inhibitors cause serotonin to accumulate in synapses, with fewer side effects than the tricyclics o Ex: Prozac, Zoloft o Too high of a dose = too much serotonin which causes mania Associated with an increased risk of suicide Anxiolytics/ tranquilizers Reduce nervous system activity Meditating/calming yourself acts on GABA receptors and causes a similar effect to anxiolytics Benzodiazepine o Benzodiazepine agonists act on GABA recAptors and enhance inhibitory effects of GABA via Cl influx o Causes hyperpolarization o Allopregnanolone endogenous benzodiazepine Barbiturates o First class of epilepsy drugs o Addictive o Noninhalation anesthetic used to put someone in a coma o Block sodium channels to prevent inflow of sodium ions o Barbiturates also increase flow of chloride ions across the neuronal membrane Together cause inhibition of neuron firing Alcohol Biphasic effect (stimulant then depressant) In low doses alcohol is a stimulant o Turns off cortical inhibition, reducing social constraints and anxiety o Causes relaxation then disinhibition o At low doses affects dopamine (DA) At higher doses alcohol has a sedative effect (depressant) o Impaired motor function, stupor, coma, then death (respiratory failure) o High doses affect GABA and NMDA Affects several neurotransmitter systems o Inhibits glutamate (excitatory) o Increasing binding of GABA at GABA receptor (inhibitory) A o Combined effect at glutamate and GABA receptors is sedation, anxiety reduction, muscle relaxation, inhibited cognitive and motor skills o Pleasurable effects come from stimulation of dopamine, opiate, serotonin, and cannabinoid receptors Seizures during alcohol withdrawal are due in part to a compensatory increase in the number of glutamate receptors over time Brain effects o Alcohol reduces brain metabolism o The brain is smaller in the alcoholic and the ventricles are larger o Alcohol damages neurons in the cerebellum and frontal lobe o Neurons can recover – brain looks closer to normal in recovering alcoholics Fetal alcohol syndrome o Alcohol has severe effects in the developing brain o Some women can drink a ton every day and have perfectly normal babies while some can drink moderately and have a child with fetal alcohol syndrome o Causes mild facial defects and microcephaly Opiates Can depress breathing by changing neurochemical activity in the brain stem o Brain stem controls automatic body functions Can change the limbic system (controls emotion) to increase feelings of pleasure Can block pain messages transmitted through the spinal cord from the body Morphine o Binds to opioid receptors in the brain stem, especially in the locus coeruleus and the periaqueductal gray o Opium contains morphine Heroin o Marketed by Bayer as a cure for codeine addiction before it was quickly discovered that heroin rapidly metabolizes into morphine Marijuana 5000 BC Indian medical practice used marijuana to treat appetite loss Active ligand is THC (tetrahydrocannabinoid) Effect o Wide range of effects o CB receptors are concentrated in brain areas that influence pleasure, memory, concentration, time perception, appetite, pain, and coordination o Negatively affects memory; impairs shortterm memory making it hard to learn complex tasks o Altered judgment and decision making o Slows reaction time – impairs driving skills o Altered mood euphoria, calmness; in high doses, anxiety, paranoia o Analgesic, decreases nausea, appetite stimulant Endocannabinoids – bind cannabinoid (CB) receptors o Anandamide and 2AG (2 arachidonoyl glycerol) o Retrograde signaling molecules released to activate cannabinoid receptors on nearby neurons o Act locally (only effect neurons in that site) because they are lipophilic (fat soluble) Can’t store in vesicles so they exist as part of the membrane o Synthesized “ondemand” Antagonist Rimonabant o Treats obesity and nicotine addiction o Many widerange effects o Withdrawn due to increase in suicide and suicidal thoughts Nicotine Primary psychoactive and addictive drug in tobacco Affects nicotinic (acetylcholine) receptors Periphery o Activates muscles and causes twitching CNS o Increases alertness and decreases reaction time o Activates nicotinic ACh receptors in the ventral tegmental area (DA) Smoking/health risk o Health risk is mostly due to other compounds in tobacco, not nicotine But nicotine is the addictive component o Smoking is the primary cause of preventable death in the world Kills 500,000/year in the US (heroin kills 400/year in US) o Withdrawal symptoms are mild o Only 5% of attempts to stop are successful; about the same statistic for heroin Cocaine Leaves from coca shrub alleviate hunger, enhance endurance and sense of wellbeing o The leaves are not addictive Cocaine, the purified extract o Crack cocaine enters the brain more rapidly o Faster speed of onset = bigger high but not as long lasting (rapid offset) highly addictive Cocaine blocks monoamine transporters, especially dopamine o Blocks reuptake of catecholamines, enhancing their effects o More serotonin, dopamine, and norepinephrine in the synaptic cleft Cocaineamphetamineregulated transcript (CART) peptide involved in pleasure sensations from these drugs and in appetite suppression o Side effect of Adderall = can’t gain weight o Goal to make an appetite suppressant that doesn’t cause addiction Cocaine increased stimulation; over short time (10 days) the brain “gives up” and see very reduced activity in the brain Amphetamine Amphetamine and methamphetamine are synthetic stimulants o Crystal meth, dextroamphetamine (slow/controlled release form) They block reuptake and increase the release of catecholamines Shortterm effects include alertness, euphoria and stamina Longterm abuse leads to sleeplessness, weight loss, and schizophrenic symptoms Stimulants for ADHD Adderall (dextroamphetamine); Ritalin (methylphenidate); Strattera (atomoxetine) Brain imaging studies show that stimulant medication increases activity in prefrontal cortex, some subcortical regions, and cerebellum all centers for executive function Corticothalamic networks control inhibitory attentional and impulse control systems and process internal and external stimuli o ADHD medications stimulate these inhibitory networks to function better Hyperactive behavior (leg tapping, fidgeting) stimulates those brain networks to work better o When the medication stimulates these networks, the hyperactive behavior becomes unnecessary and is reduced LSD Resembles serotonin Not addictive Increases activity in the visual cortex Effects o Unpredictable depend on amount taken, the user’s personality, mood and expectations, and surroundings in which the drug is used o Include dilated pupils, higher body temperature, increased heart rate and blood pressure, sweating, loss of appetite, sleeplessness, dry mouth, and tremors o May feel several different emotions or change quickly from one emotion to another o Produces delusions and visual illusions o Sense of time and self changes o Sensations seem to “cross over,” giving the user the feeling of hearing colors and seeing sounds PCP (phencyclidine) Glutamate NMDA receptor antagonist PCP produces feeling of depersonalization and detachment from reality o bizarre injuries; false sense of being able to do things that aren’t possible Its many side effects include combativeness and catatonia (can’t move/speak) Ecstasy (MDMA) Amphetamine analog/derivative o Less potent than amphetamine Primary effects in brain are on neurons that use serotonin MDMA blocks the serotonin reuptake transporter o prolonged serotonin signal excessive release of serotonin o oxytocin release Mothers naturally make oxycontin after giving birth – bonding to child Social bonding drug raves Khat Native to East Africa/Arabian Peninsula cultural tradition for many social situations Flowering shrub abused for its stimulantlike effect 2 active ingredients: cathine and cathinones Effects are similar to other stimulants, such as cocaine and amphetamine “Bath salts” “Bath salts” describes a family of manmade chemicals related to cathinone Usage is stable at about 1% of high school juniors and seniors As governments outlaw each current “bath salt” chemical, chemists synthesize new ones GHB (Gammahydroxybutyric acid) = the generic drug oxybate (FDAapproved medication = Xyrem) Used to treat narcolepsy Analogues are available legally as industrial solvents At bars or rave parties, GHB is sold in liquid by the capful for $5 to $25 GHB and its analogues increase libido, suggestibility, passivity, and cause amnesia users are vulnerable to sexual assault (daterape drug) Rohypnol = flunitrazepam Not made in the U.S. “Not trending” – old version of the daterape drug The tablet can be swallowed whole, crushed and snorted, or dissolved in liquid Adolescents abuse Rohypnol to produce euphoria Cocaine addicts use
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